AC5 Knockout in Mice Increases Exercise Performance as Well as Extending Life

Here I'll point out some of the latest work on adenylate cyclase 5 (AC5), a longevity gene in mammals, which is now shown to boost exercise performance as well as longevity in mice. It is an open question as to the degree to which the longevity effects are secondary to the exercise effects. The authors of this paper note that there has been little study of exercise effects for most of the other methods of enhancing longevity in laboratory mice, which is an interesting oversight. Perhaps this will change with a growing interest in the development of exercise mimetic drugs.

Disruption of AC5, such as through gene knockout, is one of the many methods shown to modestly slow aging and extend healthy life in mice. As for all of these approaches, much work is yet needed to understand exactly how it works under the hood. The present high level understanding of single gene longevity enhancements in laboratory animals varies from sketchy theory to fairly robust outline, and getting any further than that is proving to be a slow, expensive, and time-consuming business. Every mechanism influences every other mechanism inside a cell, nothing happens in isolation, and so understanding any one life-extending genetic alteration blurs at the edges into the much, much larger project of understanding the enormous complexity of cellular biochemistry as a whole.

The major finding of this investigation is that disruption of AC5, which actually decreases sympathetic tone, increases exercise performance. This is novel, as the most common mechanism mediating enhanced exercise is via increased sympathetic stimulation and catecholamines, resulting in increased AC activity and augmented cardiac output. This was not the mechanism in AC5 knockout mice, where AC activity is actually reduced, and there was no greater increase in cardiac output during exercise compared with WT mice, based on direct measurements of ascending aortic blood flow with implanted ultrasonic flow probes and heart rate in chronically instrumented mice. Further confirming the lack of a cardiac mechanism, the cardiac-specific AC5 knockout did not exhibit enhanced exercise. Accordingly, the mechanism resided at the level of the exercising skeletal muscles, which was confirmed, when we found that exercise performance was also elevated in the skeletal muscle-specific AC5 knockout.

Another key finding of the current investigation was demonstrating that protection against oxidative stress, by increased MnSOD levels and activity in AC5-deficient skeletal muscles, is also involved in the mechanism of enhanced exercise capacity in AC5 knockout mice, as exercise capacity of AC5 knockout mice was significantly attenuated in AC5 knockout / MnSOD heterozygous knockout bigenic mice. One question that arose is whether these effects of enhanced exercise in AC5 KO mice are simply due to a decrease in AC, which might be evoked in a knockout from any of the 9 AC isoforms, or are they due to unique signaling in AC5. To address this question, we examined exercise in 10 AC6 KO mice and 7 wild type controls. The AC6 KO mice did not show increased distance or speed with exercise compared to their wild type. Therefore, the enhanced exercise was not simply due to a reduction in AC, but was rather unique to the AC5 KO and its signaling pathway noted above.

Exercise plays an essential role in longevity, in general, and healthful aging, in particular, as it protects not only against obesity, diabetes, and cardiovascular disease, but also reduces the risk of cancer and improves bone health and even mental diseases that impair aging. Therefore, the demonstration of improved exercise performance in the AC5 knockout model is particularly germane, as this is also a model for longevity, and protects against cardiovascular stress, diabetes, and obesity. In view of the important link between exercise and longevity, it is surprising that of 20 mouse models we reviewed, only two studied exercise and found it to be increased.



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